This program focuses on newly identified features of AD pathobiology, having particular relevance to sporadic AD (SAD) and the role of vascular risk factors. The overall goal is to test the hypothesis that endocytic pathway (EP) and lysosomal system (LS) abnormalities, which include the earliest pathological changes yet demonstrated in SAD brain, are centrally involved in amyloidogenesis and neurodegeneration in SAD and are a critical link between vascular and parenchymal pathology in AD. The Program's main objectives are to elucidate underlying cellular mechanisms in AD by developing imporoved mouse models of AD, particular SAD, and of vascular pathology and by applying biochemical, cell biological, morphometric, and in vivo MR imaging approaches to these models. The first project investigate abnormalities of neuronal endocytosis and increased protease trafficking to early endosomes and purified endosome fractions will be analyzed in relation to disease onset and progression. Transfected cells and transgenic and mutant mice that model EP and protease trafficking alterations will be characterized to establish how these abnormalities influence Abeta formation and clearance and the survival of neurons and vascular endothelia. Another project tests the hypothesis that neuronal LS activation promotes cell atrophy and neurodegeneration. The onset and progression of LS activation in relation to other AD neuropathology and APOE genotype will be determined in SAD brain. Antecedents to LS activation and relationships to neuropathology will be evaluated in transgenic FAD mouse selectively modulated. Mechanisms underlying lysosome- mediated cell death will be defined. Another project, ischemia models and transgenic mouse models of cerebral amyloid angiopathy and of human APOE will be used to clarify how vascular injury and ApoE isotype modulate EP and LS abnormalities and promote AD neuropathology. Abeta clearance will be studied in vivo in AD and vascular mouse models and in vitro in organotypic models of the human and mouse BBB. The last project, longitudinal MR imaging will be applied to transgenic mouse models to characterize the effects of progressive beta-amyloid deposition on brain structure and function. The measures, which are directly translatable to human imaging studies and other mouse models, including brain regional volumes, cerebral perfusion (blood flow), and diffusion quantitative neuropathology. It is anticipated that this Program will establish improved animal models for drug discovery, advance clinical diagnosis by MR imaging, and define novel cellular mechanisms of pathogenesis that will be the basis for AD therapies.